Glucagon is a 29-amino acid pancreatic hormone which is secreted from the pancreatic a cells into the portal blood supply in response to hypoglycemia and acts as a counterregulatory hormone to insulin. Most of the physiological effects of glucagon are mediated by its interaction with a glucagon receptor in the liver, followed by activation of adenylate cyclase to increase the intracellular cAMP levels. The result is an increase in glycogenolysis and gluconeogenesis, while attenuating the ability of insulin to inhibit these metabolic processes (Johnson et al., J. Biol. Chem. 1972, 247, 3229-3235). As such, the overall rates of hepatic glucose synthesis and glycogen metabolism are controlled by the systemic ratio of insulin and glucagon (Roden et al., J. Clin. Invest. 1996, 97, 642-648; Brand et al., Diabetologia 1994, 37, 985-993).
Diabetes is a disease characterized by elevated levels of plasma glucose. Uncontrolled hyperglycermia is associated with an increased risk for microvascular and macrovascular diseases, including nephropathy, retinopathy, hypertension, stroke, and heart disease. Control of glucose homeostasis is a major approach to the treatment of diabetes. It has been demonstrated in healthy animals as well as in animal models of types I and II diabetes that removal of circulating glucagon with selective and specific antibodies resulted in reduction of the glycemic level (Brand et al., Diabetologia 1994, 37, 985-993; Brand et al., Diabetes 1994, 43(Suppl. 1), 172A). Therefore, one of the potential treatments for diabetes and other diseases involving impaired glycemia is to block a glucagon receptor with a glucagon receptor antagonist to improve insulin responsiveness, to decrease the rate of gluconeogenesis, and/or to lower plasma glucose levels by reducing the rate of hepatic glucose output in a patient.